Methods of producing an electrochemical sensor for determining an analyte concentration

ABSTRACT

The invention relates to an electrochemical sensor for the determination of a concentration of at least one analyte in a medium, in particular a body tissue and/or a body fluid, to an apparatus that includes the electrochemical sensor, and to a use of the electrochemical sensor, and finally to a method for producing it. The electrochemical sensor has an isolation element and at least two electrodes. The at least two electrodes comprise at least one working electrode and at least one further electrode, in particular at least one counter electrode and/or at least one reference electrode. The at least two electrodes run parallel to one another and form an electrochemical measuring cell of the electrochemical sensor.

CLAIM OF PRIORITY

The present application is a continuation based on and claiming priorityto PCT/EP2007/058074, filed Aug. 3, 2007, which is based on and claimspriority to German Patent Application No. 102006037328.6, filed Aug. 8,2006 and European Patent. Application No. 06123227.8, filed Oct. 31,2006 which are hereby incorporated by reference in their entirety.

TECHNICAL FIELD OF THE INVENTION

The invention relates to an electrochemical sensor for the determinationof a concentration of at least one analyte in a medium, in particular abody tissue and/or a body fluid, and further to an apparatus with whichthe electrochemical sensor is used, to a use of the electrochemicalsensor and of the apparatus, and to a method for producing theelectrochemical sensor. Such sensors or apparatuses are used, inparticular, in the field of medical technology, for example in order todetermine electrochemically a concentration of glucose (in particularblood glucose or glucose in a tissue fluid), lactate or other analytes,in particular metabolites.

BACKGROUND

The determination of the blood glucose concentration, and thecorresponding medication is an essential item of the daily routine ofdiabetics. In this case, the blood glucose concentration needs to bedetermined quickly and easily several times a day, typically 2 to 7times, in order to be able to take appropriate medical measures whenrelevant. In many instances, a modification is performed in this processby means of automatic systems, in particular with the aid of insulinpumps.

In order not to restrict the daily routine of the diabetic more than isabsolutely necessary, use is frequently made of appropriately mobileunits that should be easy to transport and to handle so that the bloodglucose concentration can be measured without any problem, for exampleat the workplace or during free time.

There are currently available various mobile units that function in partaccording to different measuring methods and with the use of differentdiagnostic methods. A first measuring method is based, for example, onan electrochemical measuring method in which a blood sample that istaken from the body tissue of the patient by perforating a skin layer bymeans of a lancet is applied to an electrode coated with enzymes andmediators. Corresponding test strips for such electrochemical measuringmethods are described, for example, in U.S. Pat. No. 5,286,362, thedisclosure of which is hereby incorporated hcrcin by reference in itsentirety. Other known measuring methods use optical measuring methodsthat are based, for example, on the fact that the substance (analyte) tobe detected can react with specific detection reagents, a change incolor of the reaction mixture occurring in the process. Systems fordetecting such color reactions and thus for detecting the correspondinganalytes are known, for example from CA 2,050,677, the disclosure ofwhich is hereby incorporated herein, by reference in its entirety.

The detection methods described are overwhelmingly based on the factthat a patient firstly takes an appropriate sample of the body fluid tobe examined, this possibly being both a blood sample and a urine sample,this then being examined appropriately by means of the test apparatus.This method includes various disadvantages, however. Thus, this methodis firstly extremely complicated and presupposes a number of handlingsteps. Thus, for example, a lancet needs to be provided and loaded,subsequently a skin layer must be perforated by means of this lancet,and then a blood drop thus produced must be applied to a test strip, andthis test strip needs to be evaluated subsequently by means of anappropriate unit. For many patients, in particular older people andchildren, these handling steps can frequently be carried out only withdifficulty, since the patients have restricted motor ability and limitedeyesight, for example. Furthermore, these method steps can be carriedout discretely only in a few instances so that, for example, protectionof the privacy of the patient during a measurement at the workplace isonly insufficiently preserved. Again, faulty operation in the course ofthe measuring method can easily lead to wrong measured valuesaccompanied, in part, by fatal consequences of a false medication builton wrong measurement results.

For this reason, there are known from the prior art systems thatgenerate continuously measured data and that can be used as analternative or in addition to the above-described systems or methods,for example in order to reduce the number of individual measuringoperations. Thus, for example, systems are commercially available thatcomprise a membrane tube in the subcutaneous tissue through which atransport liquid is pumped. Via the membrane, glucose diffuses into thetransport liquid, which is then in turn conveyed to an electrochemicalmeasuring cell. The glucose concentration is then measured in theelectrochemical measuring cell. However, there is the disadvantage withsuch an arrangement for continuously producing measured values that itrequires the patient to always carry along a supply of transport liquidand an appropriate waste container for holding contaminated transportliquid.

Further sensor types, known from the prior art, for continuouslyproducing measured values are configured to be implanted in a bodytissue; for example, U.S. Pat. No. 6,892,085 B2, the disclosure of whichis hereby incorporated herein by reference in its entirety. Generally,such continuous monitoring set ups comprise an encapsulated glucosesensor system that comprises a glucose sensor and a protective capsule.In this case, three electrodes, a working electrode, a counter electrodeand a reference electrode are provided that are applied to one side of asubstrate. To improve implantability, this electrode arrangement can beintegrated in a hollow needle that is used as an insertion aid topuncture body tissue. After the insertion, the hollow needles arewithdrawn from the tissue again and only the sensors remain in the bodytissue. Other exemplary systems are described, e.g., in U.S. Pat. No.5,591,139, the disclosure of which is hereby incorporated herein byreference in its entirety.

A main advantage of the continuously measuring systems is that it isalso possible to detect relatively short periodic fluctuations in theglucose concentration (time profiles) in conjunction with the intake offood and physical exercise. This is of great significance for “setting”of a diabetic.

The implantable sensors known from the prior art are, however, extremelycomplicated with regard to their design and production. If it ispresupposed that these sensors are disposable sensors that can be usedonly for a short time (typically approximately one week), it thenbecomes clear that the methods used in the case of the sensors knownfrom the prior art do not meet the requirements placed on disposablearticles. Thus, for example, a complicated micro-structuring method, inparticular a lithographic method, is required to produce the sensorknown from U.S. Pat. No. 5,591,139. However, such methods cannot becombined with the production of cost-effective disposable articles.Again, complicated structuring methods are required to produce thesensor known from U.S. Pat. No. 6,892,085 B2, since the electrode padsmust be structured carefully. In view of the small size of theseelectrodes, lithographic methods are likewise required therefor, andthis in turn drives up the costs for producing such sensors.

Again, lithographic methods, in particular the etching of metal layersassociated with these methods, are not always as reliable as is requiredfor producing medical products. In particular, it can occur from time totime that individual electrodes are still interconnected by “bridges” orwebs such that the functionality of the sensors can be slightly impairedor even completely negated, because of production problems. A furtherdisadvantage of the sensors known from the prior art, such as areapparent from U.S. Pat. No. 6,892,085 B2 and U.S. Pat. No. 5,591,139,for example, consists in the use of a hollow needle or in the use of acapillary.

Instead of the previously described implantable sensors, in the case ofwhich micro-structuring methods are used to structure the electrodepads, for example a lithographic method, implantable sensors, forexample those known from WO 90/10861, the disclosure of which is herebyincorporated herein by reference in its entirety, can be formed in awire-shaped fashion. That is, individual wires can be embedded in anisolating mass. The active measuring surfaces are respectively the endfaces of the wires inside a plane that is exposed by a separatingoperation or the like. Such sensor systems are capable of multiple use,and can be used in an appropriate measuring instrument. The sample isapplied inside the measuring instrument to the previously exposed endfaces of the wires (in vitro measurement). Another example of systemsemploying wire-shaped sensors is disclosed in U.S. Pat. No. 4,805,624,the disclosure of which is hereby incorporated herein by reference inits entirety.

The above-discussed solutions in accordance with the prior art makecontact with a body tissue only in a very restricted area. The electrodearrangement, usually comprising a working electrode, a counter electrodeand a reference electrode, is very restricted locally, that is to say iscapable of recording informative results only in a very small area ofthe body tissue. The functioning of the sensors known from the priorart, which can also be implanted, can be disturbed by local tissueinhomogeneities such as, for example, wound effects or fat deposits.Furthermore, sensor membrane characteristics can have a negative effecton the measured values. The electrode pads from other known systems haveelectrodes which lie next to one another in one plane and in the case ofwhich the required miniaturizability is substantially restricted as afunction of the selected micro-structuring methods. The disadvantage ofthe sensors known from the prior art, which can also be implanted, is tobe seen in that it is impossible to make use of cost-effectiveproduction methods that are required for large batch production andcould be used in the course of mass production.

SUMMARY

In accordance with the solution proposed according to the invention, anelectrochemical sensor is proposed for the determination of aconcentration of at least one analyte in a medium, in particular in abody tissue and/or a body fluid. The electrochemical sensor is generallyconfigured in such a way that it can be implanted in a body tissue,and/or can be inserted subcutaneously. For this purpose, at least theexposed sensor surface is therefore configured to be biocompatible suchthat, in particular, no cytotoxins can diffuse into the body tissue, orcome into contact with the body tissue.

The analyte can be, for example, glucose, lactate, hormones or otheranalytes that play a role in medicine, in particular. Alternatively, orin addition the electrochemical sensor can, however, also be used tomeasure other types of analytes. In particular, the sensor is based onthe use of an electrochemical measuring method.

A basic idea of the invention consists in configuring theelectrochemical sensor such that an arrangement of at least two thinwires forms an electrochemical measuring cell. The arrangement of thinwires simultaneously provides the electrical connection to a suitablemeasuring electronics. The measuring of the analyte concentration isthen performed after the use of the electrochemical sensor byelectrochemical (for example amperometric) measuring methods between theat least two electrodes—a working electrode and a counterelectrode—particularly by means of a DC voltage. A reference electrodefor currentless measurement of the working electrode potential can beused, in addition.

In order to achieve the most compact design possible for theelectrochemical sensor, the individual electrodes of the electrodearrangement are aligned with one another, at least in one section, insubstantially parallel fashion (that is to say an angular deviation ofthe parallel by not more than about 5° and even not more than 1°), andare generally isolated from one another by an isolation element. It ispossible in this way to achieve more advantageous characteristics of theelectrochemical sensor, because the sensor exhibits a typically goodhomogeneity along its longitudinal extent. In particular, the cell widthof the sensor (that is to say thickness of the layers, electrode spacingetc.) exhibits a high uniformity and low tolerances.

The electrode arrangement generally comprises at least two electrodes,there being at least one working electrode and at least one furtherelectrode, the at least one further electrode being intended to compriseone or both of at least one counter electrode and at least one referenceelectrode. In the case of the electrochemical sensor proposed accordingto the invention, the working electrode and the at least one furtherelectrode are separated from one another by an isolation element.Alternatively or in addition, it is also possible for the electrodes tobe embedded directly, completely or partly, in an isolation material. Inthe case of the electrochemical sensor proposed according to theinvention, the isolation element of the electrochemically operatingelectrochemical sensor is represented by an electrically non-conductingmaterial such as, for example, a plastic material.

Reference may be made to the following statements as regards thedefinition of the terms “isolation element” and “isolating”. Accordingto them, a direct contact of the electrodes with one another should beavoided. Of course, any isolation is only conditionally perfect, that isto say provided with an infinite resistance. Currents that do not flowthrough a transition between electrodes and electrolytes are generallydenoted as leakage currents and corrupt the actual electrochemicalmeasurement. Leakage currents are formed by the connected electronics,the plug and socket connection and in the sensor body itself. Leakagecurrents should generally be lower by a factor of one thousand than theactual sensor current.

The inventively proposed electrochemical sensor can be advantageouslydeveloped according to the invention in a very different way. Thedescribed advantageous developments can in this cast be usedindividually or in combination with one another.

Thus, the proposed electrochemical sensor can have at least one coatingmaking electrical contact with at least the at least one workingelectrode. Whereas the at least one working electrode is typicallyproduced from a material suitable for electrochemical purposes such as,for example, gold, silver, palladium, platinum or carbon, and the wirecomprising the counter electrode can remain uncoated, and likewise beproduced from a material made from one of the abovementioned materialssuitable for electrochemical purposes. If a reference electrode isfashioned on the electrode arrangement of the inventively proposedelectrochemical sensor, said reference electrode is typically an ionelectrode of the second type that can be fashioned from a silver wirecoated with silver chloride on its surface.

An electrode can be defined in this case as an interface between a firstorder conductor (charge transport by electrons in metal) and a secondorder conductor (charge transport by ions in an electrolyte). Use shouldgenerally not be made for the electrodes (first order conductor incontact with second order conductor) of any materials that passivate atthe surface (form insulating oxide layers) such as, for example,aluminum. Working electrode and counter electrodes are redox electrodes,and so typically materials are chosen for electrodes comprising firstorder conductors that do not corrode or otherwise disintegrate in theevent of polarization.

On account of the configuration of the at least one working electrodeused and of the at least one counter electrode used, a slender design ofthe electrochemical sensor is possible for an inventive electrochemicalsensor within the scope of the proposed electrode arrangement. Thisparticular geometric shape enables the parallel placement of the atleast one working electrode parallel to the at least one counterelectrode, the result being to reduce substantially the action of thetissue inhomogeneities described at the beginning on the measurementresult produced by the electrochemical sensor. Owing to the inventivelyproposed configuration of the electrode arrangement as three-dimensionalgeometry, the diameter of the sensor of compact design can be kept verysmall. The electrode surface required by the signal level can beprovided on the basis of the peripheral surface of the electrodearrangement having at least one working electrode and at least onecounter electrode.

In one embodiment, the proposed electrochemical sensor comprises threeelectrodes of wire-shaped formation that are isolated from one anotherby an isolation element using Y geometry. The isolation element using Ygeometry is generally present as a plastic press-drawn section and can,as described below in even greater detail, be used in the course oflarge batch production when the inventively proposed electrochemicalsensor is being produced. An isolation element using Y geometry providesthe possibility of providing three holding compartments for holding theat least one working electrode, the at least one counter electrode andthe reference electrode that is possibly used for measuring the workingelectrode potential. The plastic press-drawn section that is typicallypresent using Y geometry and forms the isolation element lends theelectrochemical sensor an adequate mechanical stability and tensilestrength. This facilitates the handling of the electrochemical sensornot inconsiderably for unpractised users, as well. The sensor can beused, for example, together with an insertion aid (for example can bedrawn under the skin with the aid of a needle, the needle being removedagain). Thus, the sensor should have a certain tensile strength for thispurpose. At the same time, however, it should be flexible so that upondeformation of the surrounding tissue (by movement or pressing on theskin) the sensor does not tear a wound in the tissue (some of whichcould result in the sensor supplying incorrect measured values, forexample). These characteristics can be ensured by using the Y geometry.

The electrode arrangement of the proposed electrochemical sensor can beprovided with a coating for immobilizing reactive components. Thiscoating for immobilizing reactive components can be applied to theindividual electrodes, that is to say at least one working electrode,the at least one counter electrode and, if appropriate, the at least onereference electrode or the finished electrode pack, which surrounds theisolation element. The electrode arrangement of the inventively proposedelectrochemical sensor can comprise apart from the electrodes and theisolation element additional barrier layers that can, for example, belayers of a polymer, in particular an insulating polymer. Examples ofsuitable polymers are polyester, polyethylene, polypropylene orpolyurethane. Other insulating polymers can also be used, it beingpossible to refer, in turn, to the above description with reference tothe term “isolating”.

The coating of the electrode pack with immobilization medium, or of theindividual electrodes of the at least one working electrode, of the atleast one counter electrode or the at least one reference electrode forimmobilizing reactive components, can be a membrane layer that exhibitsa partial permeability to the at least one analyte. The membrane layercan exhibit a permeability for glucose, lactate and/or further analytesto be detected. The membrane layer that can be used to coat theelectrode pack or the individual electrodes mentioned should beimpermeable to auxiliary chemicals used in the electrochemical measuringmethod, so that, for example, enzymes that are applied to one or more ofthe electrodes mentioned and partly exhibit a toxicity do not pass intothe body tissue and do not contaminate the latter.

The membrane layer to be applied in order to immobilize reactivecomponents that, for example, surround the electrode arrangement in theform of an envelope or enclose in the form of an envelope the individualelectrodes of the electrode arrangement—the at least one workingelectrode, the at least one counter electrode and the at least onereference electrode. The applied coating of immobilization medium can,for example, have a polyurethane. A multilayer membrane layer structureis also possible. The coating of immobilization medium having, forexample, a polyurethane can be applied here using a coating method suchas, for example, an immersion method, a spray method, or an annularnozzle coating.

The configuration of the electrode arrangement for the electrochemicalsensor can be performed in various ways. In particular, as describedabove, the at least two electrodes can comprise at least one workingelectrode and at least one further electrode that has at least onecounter electrode and at least one reference electrode. In particular,the at least one counter electrode should be configured in such a waythat the counter electrode enables an electrochemical redox reactionthat permits a flow of current through the entire measuring cell. If,for example, an electrode reaction leads to electrons, the redoxreaction at the respective other electrode should remove thecorresponding number of electrons. The actual redox reactions can becompletely independent of one another in this case. This redox reactionshould typically not limit the current in such a way in this case thatthe detection reaction at the working electrode is no longer graduatedover the entire concentration range (only two electrodes and anamperometric measuring method). In the case of a three electrode controlwith a fed-back reference electrode measuring section, the total cellvoltage necessary for maintaining the counter electrode redox reactionshould not overshoot the dynamic control range of the controlelectronics.

A counter electrode and a reference electrode can also be formed as acommon electrode. The individual electrodes of the electrode arrangementcan be coated with enzymes or other chemical auxiliaries that arerespectively selected specifically as a function of the analyte to bedetected. Thus, for example, in order to detect glucose it is possibleto use glucose oxidase (GOD), which converts glucose intogluconolactone. The charge carvers thereby released are detected. Inorder to enable this detection, use is made of materials which reduceovervoltage and mediate charge, and that function rather like “chargemediators” between the medium and the electrodes. Materials that reduceovervoltage and mediate charge (such as manganese dioxide, for example)are also denoted as electrochemical redox catalysts.

Since the components of the on the detection reaction chain of thesensor can be dangerous for health, however, there is a need in manyinstances to immobilize these components in order to use anelectrochemical sensor. For example, a covalent bonding to theelectrode, and/or a layer of the electrode, for example a metal layer,can take place for the immobilization. This technique can be used, inparticular to immobilize mediators. A further possibility consists inintegrating the components wholly or partly in an insoluble layer thatis insoluble in the fluid surrounding the electrochemical sensor in theimplanted state, in particular the body fluid. It is also possible touse other types of redox mediators in common with respectively suitableenzymes for the specific detection of the respective analytes.

In addition to the configuration described for the at least one workingelectrode, it is also possible to configure the at least one referenceelectrode, and/or configure the at least one counter electrode invarious ways. Thus, the at least one reference electrode should have anelectrode system with an electrochemical potential that does not change,or changes only insubstantially, in a working range of theelectrochemical sensor. Thus, for example, given a typical voltage load,i.e. a voltage between the working electrode and the reference electrodeof typically no more than 400 mV, the electrochemical potential of theat least one reference electrode should generally change by not morethan ±5 mV. It is ensured in this way that the reference electrode actsas true reference with whose potential the electrochemical potential ofthe at least one working electrode can be compared. In principle, it ispossible to use suitable materials and/or material combinations for thereference electrode. A silver/silver chloride (Ag/AgCl) electrode systemhas proved to be particularly advantageous in this case. Other electrodesystems can also be used in principle.

The at least one counter electrode of the proposed electrode arrangementfor the inventively proposed electrochemical sensor can be configured ina multiplicity of various ways. In one embodiment, the at least onecounter electrode is configured in a wire-shaped fashion in order toobtain a slender design of the electrode arrangement. However, it shouldbe ensured in this case that the at least one counter electrode isconfigured in such a way that the at least one counter electrode enablesan electrochemical redox reaction that permits a flow of current throughthe entire measuring cell. When an oxidation takes place at the at leastone working electrode, a reduction should take place at the at least onecounter electrode of the electrode arrangement, and vice versa. Inprinciple, it is possible to use pure metals as counter electrodes suchas, for example, platinum. However, this has the disadvantage that gastypically forms at such metal electrodes, for example hydrogen or oxygenforms. By way of example, gas forms in aqueous media at noble metalssuch as platinum when the redox reactions that are mandatory for therequired transport of current can only be an electrolysis of water, thatis to say there are in the electrolyte no sufficient concentrations ofother redox-active species that can proceed within the potentials of theelectrolysis of water. However, such a formation of gas is in somecircumstances associated with difficulties in design, that is to say thedesign of the sensor must either be adapted to this formation of gas, orsuch a formation of gas must be avoided. To this extent, when anelectrode system, in particular a redox electrode system, is used in thecase of which the formation of gas is avoided, it is possible in thiscontext to use the Ag/AgCl electrode system in an advantageous way. AgClis reduced, for example, in this case. It may be seen in this that theat least one counter electrode is consumed during operation of theelectrochemical sensor. If the at least one counter electrode has beenconsumed, gas frequently forms in turn, and so during operation theelectrochemical sensor generally has a limited service life.Consequently, it is also advantageous when the at least one counterelectrode of the proposed electrode arrangement is configured with asubstantially larger actual electrode surface than the at least oneworking electrode of the electrode arrangement.

The proposed electrochemical sensor or an apparatus that includes suchproposed electrochemical sensor is used generally for continuousdetermination of a concentration of at least one analyte in the bodytissue and/or a body fluid. Here, “continuous” can be understood, forexample, to mean that analyte concentrations are determined over aspecific measurement period, for example one week, at regular intervals(thus, for example, every five minutes or every hour) or elsepermanently, that is to say with a temporal resolution that is limitedonly by the temporal resolution of a measuring instrument. However,during a continuous measurement there is a problem that over themeasurement period the apparatus that comprises the inventively proposedelectrochemical sensor can drift. A drift generally occurs when as aresult of use the rate constant of one of the rate-determining steps inthe entire reaction chain is varied. This can, for example, be areducing enzyme activity, something which is, however, only the case asa rule when this determines the reaction rate. If possible, the enzymeshould be dosed such that a buffer is present over the storage time andperiod of use. A change in the diffusion properties of a membrane duringthe period of use often has the strongest effect. A further problem isnonlinear dependencies of the measuring current on the glucoseconcentration, the function curve varying during storage times andperiods of use. One of the rate-determining steps is then limiting herestarting from a specific required turnover starting from a determiningglucose concentration. Usually, a continuous measurement is performed byvirtue of the fact that a “conventional” measuring method, for examplethe taking of a blood drop and measurement of the blood glucoseconcentration, is firstly used to carry out a reference measurement thatis then compared with the measured value supplied by the implantedsensor. Subsequently, a measurement is performed over the measurementperiod on the basis of the initial reference measured value.

Furthermore, the invention proposes an apparatus for the determinationof a concentration of at least one analyte in a medium, in particular abody tissue and/or a body fluid. The inventively proposed apparatuscomprises at least one electrochemical sensor in accordance with theabove description and possible refinements thereof. Furthermore, the atleast one apparatus comprises at least one voltage measuring device formeasuring a voltage of the at least one working electrode and the atleast one reference electrode. Alternatively or in addition, at leastone current measuring device can be provided for measuring a currentbetween the at least one counter electrode and the at least one workingelectrode. In addition, the apparatus can comprise a control devicewhich is configured in such a way that the current between the at leastone counter electrode and the at least one working electrode iscontrolled in such a way that the voltage measured between the at leastone working electrode and the at least one reference electrode isprecisely equal to a prescribed desired voltage.

The described proposed electrochemical sensor can be used, for example,for a continuous determination of a concentration with the aid of atleast one analyte in the body tissue and/or a body fluid. For thispurpose, it is possible by way of example to implant the inventivelyproposed electrochemical sensor in the body tissue, for example ascomponent of the inventive apparatus in one of the describedconfigurations, doing so by puncturing. Subsequently, the sensor can bemade available for a specific time within which at least an approximateequilibrium is set in the region of the sensor and the surrounding bodytissue. Subsequently, the user can carry out a calibration measurementin the case of which, as described above, an analyte concentration inthe body fluid, for example a glucose concentration in a blood drop, isdetermined by means of a conventional method. The data therebydetermined are transmitted to the inventive apparatus, for example bymanual input or by electronic data transmission, for example by means ofa cable or by means of a wireless connection. A calibration point isthereby made available to the apparatus, and the inventive apparatus canoffset the input measured values against measured values that aresupplied by the implanted sensor. Subsequently, the implanted sensor andthe inventive apparatus can be used, for example, over a period of aweek, a measurement being performed, for example, every 5 minutes orelse without interruption. The measured values determined by theinventive apparatus can, for example, be output to the patient, or theycan also be made available to other systems, for example medicationsystems. Thus, the inventively proposed apparatus can be directlyconnected to an insulin pump that adapts an insulin dose to the measuredblood glucose concentrations. Upon expiry of the measuring time, thecomplete apparatus can be exchanged, or it is also possible to exchangeonly the inventively proposed electrochemical sensor for a new, unusedsensor.

It is also possible to implement a direction of data transmission thatis reversed in relation to the above description. Thus, for example, theapparatus with implanted electrochemical sensor can be worn wholly orpartly on the body. A calibration device can be provided separately tosaid apparatus or else as a component thereof (the inventive apparatuscan be of multipart design) (for example as a separate hand unit), inorder to undertake the described conventional calibration measurement(also denoted as “spot monitoring”). This calibration device canfunction, for example, as “master” unit to which the data determinedwith the aid of the implanted sensor are transmitted. It is thenpossible, for example, to provide a data memory, display elements andoperating elements in the calibration device, and further evaluations ofthe measured data can be carried out.

Furthermore, a method is proposed for producing an electrochemicalsensor, in particular an electrochemical sensor in accordance with theabove description, which is suitable for the determination of an analyteconcentration in a medium, in particular in body tissue and/or a bodyfluid. The method has the following steps, there not necessarily being aneed to carry out the steps in the following sequence as quoted. Again,various method steps can be repeated and carried out in parallel, and itis possible to carry out additional method steps (not listed).

The production of the electrode arrangement for the inventively proposedelectrochemical sensor can be performed by using effective,cost-effective production methods. In a first production step, the atleast one working electrode of the inventively proposed electrodearrangement, which is typically produced from a material suitable forelectrochemical purposes, such as, for example, gold, palladium,platinum and/or carbon, is coated with a reagent suitable for detectingthe analyte. This can be performed during an annular nozzle coating, theannular nozzle that is used in the course of the annular nozzle coatingand having a circular cross section enclosing at least one workingelectrode in annular fashion, and it being possible to carry out acoating of the entire peripheral surface of the at least one workingelectrode in one work operation. During this production step, the atleast one working electrode forms a long endless wire that isadvantageously capable of being coated on all sides and with a uniformfilm or coating thickness in the course of an annular nozzle coating. Oncompletion of annular nozzle coating of the at least one workingelectrode, the at least one, coated working electrode traverses a dryingstation that is formed in one embodiment as a hollow cylinder, and sothe at least one, coated working electrode traversing the drying stationis uniformly dried.

The at least one, now coated working electrode, if appropriate the atleast one reference electrode and, furthermore, the at least one counterelectrode, which can remain uncoated, and can be produced from amaterial suitable for electrochemical purposes such as, for example,gold, silver, palladium, platinum or carbon, are assembled in asubsequent method step. In addition to said three electrodes of theelectrode arrangement, the isolation element is also fashioned in thecourse of the assembly of the three said electrodes. The isolationelement, which can have a Y or star geometry, for example, is in oneembodiment an extruded section that is produced from plastic and, forexample, by microextrusion. If, for example, an extruded section of Ygeometry is used, three holding pockets advantageously result into whichthe at least one working electrode, the at least one counter electrodeand the at least one reference electrode can be inserted.

An electrode arrangement is obtained in pack form after the assembly ofthe extruded section, that is to say the isolation element, and the atleast one working electrode, the at least one counter electrode and theat least one reference electrode. In a subsequent production step, thiselectrode arrangement in the form of a pack can be fed through animmobilization medium coating in order to immobilize the reactivecomponents in the course of a further processing operation configured inone embodiment as an annular nozzle coating method. The application ofthe immobilization medium coating in order to immobilize reactivecomponents, which can be undertaken in one embodiment with the aid of anannular nozzle coating method for applying the immobilization mediumcoating in one work operation on the entire circumference in accordancewith the electrode pack obtained in the previous work step, can alsoalternatively be executed at the individual electrodes, that is to saythe at least one working electrode, the at least one counter electrodeand the at least one reference electrode.

After the membrane coating method for applying a membrane in order toimmobilize the reactive components, the electrode arrangement obtainedin the form of a pack is fed to a cut-to-length operation. Cutting tolength is understood below as the separation of the electrode pack thatis present in endless form and provided with an immobilization mediumcoating, the electrode pack having the isolation element, which isolatesfrom one another the at least one working electrode, the at least onecounter electrode and the at least one reference electrode. The cuttingto length of this electrode arrangement present in endless form isperformed by cutting individual sections of the electrode arrangement inthe form of a pack. Variable lengths can be separated in accordance withthe cut-to-length operation, it being possible for one end of theelectrode arrangement obtained, that is to say a section, to be mounted,for example, in a suitable insulation displacement connector. The otherend of the separated section can be encapsulated in a positive lockingpart that also takes over other necessary functions of anelectrochemical sensor such as, for example, insertion in the bodytissue.

The invention is to be explained in more detail by the following figuresand examples.

BRIEF DESCRIPTION OF THE DRAWINGS

The following detailed description of the embodiments of the presentinvention can be best understood when read in conjunction with thefollowing drawings, where like structure is indicated with likereference numerals and in which:

FIG. 1 shows a cross section through an insulation displacementconnector for making electrical contact with the electrode arrangementof the disclosed electrochemical sensor.

FIG. 2 shows a schematic side view of the proposed apparatus for thedetermination of an analyte concentration in a medium, with an insertionhead and the insulation displacement connector.

FIG. 3 shows an arrangement for coating an individual electrode of theelectrode arrangement in order to apply a reagent medium suitable fordetecting an analyte, with downstream drying station.

FIG. 4 shows the assembly of the at least one working electrode, the atleast one counter electrode, an isolation element and a referenceelectrode to form an electrode arrangement.

FIG. 4.1 shows a section through the isolation element.

FIG. 5 shows an annular nozzle coating station for applying to theelectrode arrangement a membrane that enables an immobilization ofreactive components.

FIG. 6 shows a cut-to-length operation of the electrode arrangementprovided with an immobilization medium coating.

FIG. 7 shows a perspective plan view of the inventively proposedelectrode arrangement.

FIG. 8 shows a schematic flowchart of the method.

FIG. 9 shows a segment of a cross-sectional illustration of the surfaceof a working electrode.

In order that the present invention may be more readily understood,reference is made to the following detailed descriptions and examples,which are intended to illustrate the present invention, but not limitthe scope thereof.

DETAILED DESCRIPTION OF EMBODIMENTS OF THE PRESENT INVENTION

The following descriptions of the embodiments are merely exemplary innature and are in no way intended to limit the present invention or itsapplication or uses.

The illustration in accordance with FIG. 1 is a section through aconnector (designed in this example as insulation displacementconnector) that comprises an electrode arrangement for anelectrochemical sensor.

The cross section, illustrated in FIG. 1, through an electrochemicalsensor 10 shows an electrode arrangement 16, 18, 20. The electrodearrangement 16, 18, 20 is surrounded by a sheath 12 that can enclose anembedding material 14. The electrode arrangement comprises at least oneworking electrode 16, at least one counter electrode 18 and at least onereference electrode 20. In the illustration in accordance with FIG. 1,the electrode arrangement 16, 18, 20 extends perpendicularly into theplane of the drawing, the at least one working electrode 16, the atleast one counter electrode 18 and the at least one reference electrode20 running parallel to one another.

The at least one working electrode 16, the at least one counterelectrode 18 and the at least one reference electrode 20 form anelectrochemical measuring cell and, at the same time, the body of theelectrochemical sensor 10. The at least one working electrode 16 isproduced from a material suitable for electrochemical purposes such as,for example, gold, silver, palladium, platinum or carbon. The use offurther noble metals or other metals or metal alloys, including inmultilayer arrangements, is also conceivable. The at least one workingelectrode 16 can be coated with a suitable reagent in order to detectthe analyte, as is described in further detail below.

The at least one counter electrode 18 is likewise produced from amaterial suitable for electrochemical purposes such as, for example,gold, silver, palladium, platinum or carbon, and can remain uncoated, orelse coated with one or multiple plies. In turn, as also in the case ofthe other electrodes, it is also possible here alternately or inaddition to make use of further metals (such as noble metals) or metalalloys or multilayer metals. The at least one reference electrode 20 isproduced in one embodiment from a silver wire that is coated on itsperipheral surface with silver chloride. The at least one referenceelectrode 20 is used for currentless measurement of the potential of theat least one working electrode.

However, it emerges from the illustration in accordance with FIG. 1 thatthere is respectively formed on the circumference of the sheath 12 ofthe electrochemical sensor 10 a connection 22 for making electricalcontact with the at least one working electrode 16, a connection 24 formaking electrical contact with the at least one counter electrode 18,and an electrical connection 26 for making electrical contacts with theat least one reference electrode 20. In the illustration in accordancewith FIG. 1, the number of connections 22, 24, 26 that corresponds tothe number of electrodes 16, 18, 20 is arranged in a circumferentialarrangement 42 that is 120° in the illustrated schematic reproducedexemplary embodiment. Depending on the number of the individualelectrodes used on the electrode arrangement 16, 18, 20, a number ofconnections 22, 24, 26 that corresponds thereto is provided on thesheath 12 of the electrochemical sensor 10. In the case of the exemplaryembodiment illustrated in FIG. 1, the at least one working electrode 16,the at least one counter electrode 18 and the at least one referenceelectrode 20 make electrical contact via contacting elements 28. Thecontacting elements 28 can be formed as insulation displacementconnecting devices that comprise a cutting edge 30. A pointed end of thecutting edge 30 formed in wedge-like fashion on the contacting elements28 respectively makes contact with the circumference of the at least oneworking electrode 16, the at least one counter electrode 18 and the atleast one reference electrode 20. An alternative to an insulationdisplacement connector, it is also possible to expose the ends of thewires and solder, bond or glue them separately to a connection board. Byway of example, this arrangement can subsequently be encapsulated, forexample in a connector housing.

It emerges, furthermore, from the sectional illustration in accordancewith FIG. 1 that the at least one working electrode 16, the at least onecounter electrode 18 and the at least one reference electrode 20 areisolated from one another by an isolation element 32. In theillustration in accordance with FIG. 1, the isolation element 32 isformed using a Y geometry, thus respectively yielding a holdingcompartment that holds the at least one working electrode 16, the atleast one counter electrode 18 and the at least one reference electrode20. The isolation element 32 is produced in one embodiment as anextruded section. Instead of the Y geometry 34 illustrated in FIG. 1,the isolation element 32 can also have another configuration, forexample a design in a X-shaped or T-shaped fashion. A cross-shapedformation of the geometry of the isolation element 32 is also possible.It should be ensured that the geometry 34 of the isolation element makessure that the at least one working electrode 16, the at least onecounter electrode 18 and the at least one reference electrode 20, whichrun parallel to one another, are separated from one another by webs bythe isolation element, for example by the isolation element 32.

The isolation element 32 illustrated in FIG. 1 in section with Ygeometry 34 comprises a first web 36, which separates the at least onecounter electrode 18 from the at least one working electrode 16. Asecond web 38 of the isolation element 32 separates the at least oneworking electrode 16 from the at least one reference electrode 20 that,in turn, is separated by a third web 40 of the isolation element 32 fromthe at least one counter electrode 18 of the electrode arrangement 16,18, 20.

An apparatus that includes the electrochemical sensor in accordance withFIG. 1 is illustrated in FIG. 2.

It may be gathered from the schematic illustration in accordance withFIG. 2 that the electrochemical sensor 10 is part of an apparatus thathas an insertion head 60. The insertion head 60 is formed with a roundedend and in one embodiment has a diameter of <about 1 mm, in otherembodiments has a diameter of <about 500 micrometers, and in yet otherembodiments has a diameter of <about 50 micrometers. The insertion head60 serves for the subcutaneous introduction of the electrochemicalsensor into a body tissue. The insertion head 60 is sealed off from theelectrode arrangement 16, 18, 20 via a first seal 32, only the at leastone working electrode 16 and the at least one reference electrode 20being, illustrated in the illustration in accordance with FIG. 2. Thedouble-headed arrow denoted by the reference numeral 70 indicates thedirection of movement in the apparatus for the determination of ananalyte concentration in a body tissue or in a body fluid.

As an alternative to the method, illustrated in FIG. 2, for inserting bymeans of the insertion head 60, other apparatuses or modes of procedurefor which no insertion head 60 is required are, however, alsoconceivable in order to insert the electrochemical sensor 10. Thus, forexample, the electrochemical sensor 10 can be inserted into the tissuevia a slotted hollow needle, it being possible instead of an insertionhead 60 to make use only of an isolation of the end face of the sensor10. Alternatively or in addition, the electrochemical sensor 10 can alsobe drawn under the skin by means of an insertion aid, for example aneedle or a blade. In this case, it is possible for example to make useof a positive locking part that serves as a driver and does not alsowithdraw the electrochemical sensor 10 again upon withdrawal of theinsertion aid. The electrochemical sensor 10 itself should, however, beconfigured in such a way that it can also be removed from a tissue againrelatively easily at the end of its use.

Aside from the insertion head 60 and electrode arrangement 16, 18, 20,the apparatus illustrated in FIG. 2 comprises an adapter 64, illustratedin cross section in FIG. 1, that, as described above in conjunction withthe exemplary embodiment of FIG. 1, can be formed as an insulationdisplacement connector. The adapter 64 ensures the electrical contactwith the at least one working electrode 16, the at least one counterelectrode 18 and the at least one reference electrode 20. The adapter 64has a circumference 66 on which electrical contact is made with theconnections 22, 24, 26, illustrated in FIG. 1, for making electricalcontact with the at least one working electrode 16, the at least onecounter electrode 18 and the at least one reference electrode 20. Asalready mentioned in conjunction with FIG. 1, the electrical contactingelements 28 can be formed as wedge-shaped elements which include cuttingedges 30 and respectively make electrical contact with thecircumferential surface of the at least one working electrode 16, the atleast one counter electrode 18 and the at least one reference electrode20. Moreover, the apparatus in accordance with the illustration in FIG.2 comprises an evaluation unit that evaluates the signals which aretransmitted via the at least one working electrode 16 and the at leastone counter electrode 18, and undertakes a determination of the analyteconcentration in the body tissue or in a body fluid and displays itdirectly to the user.

It may be mentioned for the sake of completeness that the course of thecut I-I corresponds to the cut, illustrated in FIG. 1, through theelectrochemical sensor 10. A second seal 68 is located between theadapter 64, which can be designed as positive locking part, and theelectrode arrangement 16, 18, 20. Depending on the cutting to length ofthe electrode arrangement 16, 18, 20, comprising at least one workingelectrode 16, at least one counter electrode 18 and at least onereference electrode 20, it is possible to implement different lengths ofelectrode arrangement 16, 18, 20 between the first seal 62, relating tothe insertion head 60, and the second seal 68, relating to the adapter64. It is possible in a fashion corresponding to the cutting to lengthof the electrode arrangement 16, 18, 20 to undertake a more or less deepsubcutaneous insertion of the electrochemical sensor into a body tissuein order to determine an analyte concentration. In this case, followingthe inventive solution the at least one working electrode 16, the atleast one working electrode 18 and the at least one reference electrode20 form the electrochemical measuring cell, which is enclosed by thebody tissue after insertion of the insertion head 60, and enables ananalyte to be detected in a body tissue or a body fluid. Because of theformation of the at least one working electrode 16, the at least onecounter electrode 18 and the at least one reference electrode 20 aswire-shaped components, the electrode arrangement 16, 18, 20 has a veryelongated surface. Consequently, because of the high, elongatedelectrode surface the electrochemical detection takes place over a largetissue area. Consequently, local inhomogeneities (for example insulatingfat cells) have a slight influence on the total current, sinceintegration is performed over a relatively large area. A high currentturnover is typically also associated with a high glucose consumption.This can lead in the tissue to instances of depletion, thus to measuredvalues that are falsely determined as excessively low. The goal istherefore not to select the electrode surface, but at the same time tocover a great deal of space in the tissue. This goal is reached, inparticular, by long, thin wires. Alternatively or in addition, theglucose consumption can also be choked by a thicker immobilizationlayer. The thinner the electrode pack is designed, the weaker as a ruleare the disturbing interactions with the body tissue (for example cellgrowth or wound healing).

A first production step of the electrode configuration as illustrated inFIGS. 1 and 2 with the aid of an electrochemical sensor is to begathered from the illustration in accordance with FIG. 3.

The inventively proposed electrochemical sensor 10 is distinguished by aproduction method that enables a use of individual production steps thatare advantageous for large batch production. The components of theelectrochemical sensor 10 are substantially the at least one workingelectrode 16, the at least one counter electrode 18 and the at least onereference electrode 20 and the isolation element 32. The production of asingle ply or multiply coating of the at least one working electrode 16,the at least one counter electrode 18 and the at least one referenceelectrode 20 is described below in more detail.

In order to detect the analyte that is to be determined in a bodytissue, the at least one working electrode 16 of the electrodearrangement 16, 18, 20 is coated with a reagent suitable therefor. Inaccordance with the illustration in FIG. 3, this coating step isundertaken in the course of an annular nozzle coating 82. For thispurpose, the at least one working electrode 16 is moved through anannular nozzle 84 in the conveying direction 80. The annular nozzle 84comprises a cavity 92 that is filled with a reagent medium 86. Theconveyance of the reagent medium 86 into the cavity 92 of the annularnozzle 84 is performed by a feed pump 90. Owing to the fact that thereagent medium 86 is applied to the cavity 92 of the annular nozzle 84,the at least one working electrode 16, which is present in wire-shapedform, is coated with the reagent medium 86 in one work operation as thecavity 92 of the annular nozzle 84 passes in the conveying direction 80by its surface 94. The reagent medium 86 can, for example, be a mixtureof manganese dioxide (brownstone), graphite and GOD (glucose oxidase),which convert glucose catalytically into gluconolactone. The at leastone working electrode 16, which leaves the annular nozzle 84 in theconveying direction 80, has a coated surface 94 formed by the reagentmedium 86 after passing through an exit opening 88 of the annular nozzle84. The film of the reagent medium 86 on the surface 94 of the at leastone working electrode 16 is dried in a drying station 100 downstream ofthe annular nozzle 84 in the conveying direction 80 of the at least oneworking electrode 16 before the production steps described below followon.

FIG. 4 shows the assembly of the at least one coated working electrodewith the at least one counter electrode, the at least one referenceelectrode and the isolation element present in slab form.

The at least one working electrode 16 coated with a reagent medium 86 inthe course of the coating step 82 in accordance with the illustration inFIG. 3 is fed as at least one working electrode 110 to an assemblystation 130. Furthermore, the assembly station 130 is fed the at leastone, counter electrode 18 and the at least one reference electrode 20.Furthermore, the assembly station 130 is fed the isolation element 32,which is typically produced as an extruded section and in one embodimenthas the Y geometry illustrated in FIG. 4.1. The now coated at least oneworking electrode 16, and the at least one uncoated or coated counterelectrode 18 and the at least one reference electrode 20 are groupedaround the isolation element 32 in the assembly station 130 such thatthe at least one working electrode 16, the at least one counterelectrode 18 and the at least one reference electrode 20 are isolatedfrom one another. The assembly station 130 leaves an electrodearrangement that comprises at least one coated working electrode 16, atleast one counter electrode 18, at least one reference electrode 20 andthe isolation element 32. The electrode arrangement 16, 18, 20 leavingthe assembly station 130 constitutes an electrode pack 132.

A further production step, which is fed the electrode pack in accordancewith FIG. 4 after the assembly, is to be gathered from the illustrationin accordance with FIG. 5. FIG. 5 shows that the electrode pack 132,which comprises the at least one coated working electrode 110, the atleast one counter electrode 18 and the at least one reference electrode20, is fed to an immobilization medium coating operation 140. In thecourse of the immobilization medium coating operation 140 illustrated inFIG. 5, an immobilization medium 142 is, for example, applied to theelectrode pack 132 running into an annular nozzle 146 in accordance withthe illustration in FIG. 5, in order to immobilize reactive components.As a result, the electrode pack is additionally isolated, and/orpoisonous components (for example the GOD acting as cytotoxin) areprevented from diffusing into the body tissue. The outside of theelectrochemical sensor 10, which comes into contact with the bodytissue, should be biocompatible (that is to say not rejected by thebody). That is a further beneficial characteristic of the immobilizationmedium 142. Alternatively or in addition, it is also possible to applyan additional layer that ensures this additional characteristic ofbiocompatibility. Again, the further materials used that come intocontact with the body tissue, for example materials for isolation in theconnector area and at the insertion end, should have correspondingbiocompatible characteristics, or be appropriately coated.

The annular nozzle 146 used in the course of the immobilization mediumcoating operation 140 comprises a cavity 150 that has an exit opening148 and is filled with an immobilization medium 142. The cavity 150 ofthe annular nozzle 146 is continuously filled with the immobilizationmedium 142, and so the entire surface of the electrode pack 132 runninginto the cavity in the conveying direction 80 is wetted by theimmobilization medium 142. The peripheral surface of the electrode pack132 that runs into the annular nozzle 146 in the conveying direction 80is provided with a coating with immobilization medium 142 at the exitopening 148 of the annular nozzle 146. The conveying direction of theelectrode pack 132 is denoted by reference numeral 144 in theillustration in accordance with FIG. 5. Reference numeral 152 denotesthe electrode pack 132 coated with the immobilization medium 142.

Instead of the electrode pack 132 that enters the annular nozzle 146 inFIG. 5 in the conveying direction 144 and comprises the at least oneworking electrode 16, the at least one counter electrode 18 and the atleast one reference electrode 20, which are isolated from one another bythe isolation element 32, it is also possible for individual ones of theat least one working electrode 16, the at least one counter electrode 18and the at least one reference electrode 20 to be fed to theimmobilization medium coating operation 140. The immobilization mediumcoating 140, which can be applied in accordance with FIG. 5, makes thecontact between the at least one coated working electrode 110 and the atleast one counter electrode 18, and the body tissue or the body fluid,as a result of which the presence of a specific analyte is to bedetermined. A cutting to length step can be gathered from theillustration in accordance with FIG. 6.

In accordance with the cutting to length operation 160 illustratedschematically in FIG. 6, the coated electrode pack 152, which isprovided in accordance with the preceding production steps and is coatedon the circumference, for example, with the immobilization medium 142,is cut to length into individual sections 164. The cutting to lengthoperation 160 is typically performed by transverse cutting of the coatedelectrode pack 152. It is possible in this process to set differentlengths 162 of the cut-to-length sections 164 depending on the purposeof application.

The insertion head 60, illustrated in FIG. 2, together with the firstseal 62 is fastened at one end to the sections 164 produced inaccordance with the cutting to length operation 160, and the connectionboard 64 illustrated in FIG. 2 and to which the connections 22, 24, 26are connected in accordance with the number of the electrodes of theelectrode pack 132, is fastened at the other end. This produces theapparatus (not illustrated to its entire length in FIG. 2) thatcomprises an electrochemical sensor 10. The electrochemical measuringcell of the electrochemical sensor 10 is formed by the peripheralsurface of the layer, applied in the course of the immobilization mediumcoating operation 140, of the immobilization medium 142. This layer madefrom immobilization medium 142 constitutes the boundary of theelectrochemical measuring cell, and the contact surface with the aid ofwhich the electrochemical sensor 10 makes contact with the body tissueor the body fluid.

A perspective view of the electrode arrangement of the electrochemicalsensor 10 is to be gathered from the illustration in accordance withFIG. 7.

It emerges from the illustration in accordance with FIG. 7 that the atleast one working electrode 16, the at least one counter electrode 18and the at least one reference electrode 20 are separated from oneanother via the isolation element 32. The isolation element 32 having aY geometry 34 in the illustration in accordance with FIG. 7 comprisesthe first web 36, the second web 38 and the third web 40. The first web36 and the second web 38 delimit a first holding compartment 174 inwhich the at least one working electrode 16 is held. The at least oneworking electrode 16 has a coating with a reagent medium 86 of a reagentfor detecting the analyte in the body tissue or in the body fluid. Itemerges from the illustration in accordance with FIG. 7 that theimmobilization medium 142 can be applied to this reagent medium 86. Inthe design variant, illustrated in FIG. 7, of the electrode arrangement16, 18, 20 of the electrode pack 132, the immobilization medium 142 isapplied to the peripheral surface of the at least one working electrode16, the at least one counter electrode 18 and the at least one referenceelectrode 20. As described previously in conjunction with FIG. 5, theentire electrode pack 132 exiting from the assembly station 130 inaccordance with FIG. 4 can also be coated as a whole with theimmobilization medium 142, which then constitutes the embedding material14 illustrated in FIG. 1.

Furthermore, it is to be gathered from the perspective illustration inaccordance with FIG. 7 that in conjunction with the third web 40 of theisolation element 42 the second web 38 delimits a third holdingcompartment 178 in which, in the exemplary embodiment in accordance withFIG. 7, the at least one reference electrode 20 is held. Finally, thethird web 40 and the first web 36 of the isolation element 32 inaccordance with the illustration in FIG. 7 delimit a second holdingcompartment 176, in which the at least one counter electrode 18 of theelectrode arrangement 16, 18, 20 is located. It emerges from theillustration in accordance with FIG. 7 that a diameter 170 of thereference electrode is of the order of magnitude of approximately 100μm, while reference numeral 172 denotes the sum of the diameters of theat least one reference electrode 20, the at least one counter electrode18 and the material thickness of the third web 40 of the isolationelement 32. The line 172 in accordance with the illustration in FIG. 7has a length of the order of magnitude of approximately 250 μm.

It follows from the said dimensions of the electrode arrangement 16, 18,20 in accordance with the perspective illustration in FIG. 7 that theproposed electrode arrangement 16, 18, 20 of the inventively proposedelectrochemical sensor 10 has very compact dimensions, and this is basedon the parallel arrangement of the at least one working electrode 16,the at least one counter electrode 18 and the at least one referenceelectrode 20 in the holding compartments 174, 176 and 178 of theisolation element 32.

A schematic illustration of the production method for producing theelectrochemical sensor, in particular the electrode arrangement, is tobe gathered from the illustration in accordance with FIG. 8.

It follows from the flowchart in accordance with FIG. 8 that in thecourse of the annular nozzle coating operation 82 the at least oneworking electrode is coated with the reagent medium 86 which constitutesa reagent suitable for detecting the analyte. The reagent medium 86,which is located downstream of the annular nozzle coating operation 82on the surface 94 of the at least one working electrode 16, is dried inthe subsequent drying step inside the drying station 100. Subsequently,the at least one working electrode 16, now coated with the reagentmedium 86 on the surface 94 is assembled with the at least one counterelectrode 18, the at least one reference electrode 20, and the isolationelement 32, produced in one embodiment by the extrusion method. Theassembly is performed in an assembly station 130. The electrode pack 132obtained from the assembly station 130 is subsequently subjected to animmobilization medium coating operation 140. In the course of theimmobilization medium coating operation 140, it is possible to apply theimmobilization medium 142 both to the electrode pack 132, obtained inthe assembly station 130, as a whole, and consequently to embed saidelectrode pack in the immobilization medium. In addition, it is alsopossible to coat the at least one working electrode 16, the at least onecounter electrode 18 and the at least one reference electrode 20separately, and to assemble these coated individual electrodes in theassembly station 130.

Either the coated electrode pack 152 or the assembled individuallycoated individual electrodes 16, 18, 20 are separated in the course ofthe cutting to length operation 160 following the immobilization mediumcoating operation 140. Sections 164 that can be formed in differentlengths 162 are produced in the course of the cutting to lengthoperation 160, the length 162 being determined by the particularapplication of the electrode arrangement for use in an electrochemicalsensor 10.

A segment of an electrode surface of a working electrode 16 is shownschematically in FIG. 9 in a sectional illustration. In this example,the working electrode has a gold wire 180. The gold wire 180 is coatedwith a reagent medium 86 in accordance with the method illustrated inFIG. 8. In this example, the reagent medium is composed of threedifferent components: conductive carbon particles 182, brownstoneparticles 184, GOD particles and/or GOD conglomerates 186 as well as abinder polymer 188. The binder polymer 188 ensures the processingcharacteristics of the reagent medium in the undried state. In thiscase, the viscosity and/or surface tension of the reagent medium 86 isset by choice of the binder polymer 188 such that said polymer can beeffectively processed in the “wet” (that is to say undried) state byannular nozzle coating 82, and forms a homogeneous, uniform layer thatadheres well to the gold wire 180. At the same time, the binder polymeris selected in such a way that it can be dried at moderate temperatureswithout, for example, GOD 186 being thermally destroyed in this dryingstep. Suitable binder polymers 188 are also provided, for example, bymixtures, for example mixtures of polymers with various solvents.

Furthermore, FIG. 9 also illustrates the layer of the immobilizationmedium 142. The latter surrounds the reagent medium 86 and prevents bodyfluid (denoted symbolically here by 190) from coming into direct contactwith the brownstone particles 184 and with the GOD particles 186, andprevents GOD from diffusing into the body fluid 190. At the same time,oxygen and glucose as analyte to be detected can diffuse from the bodyfluid 190 through the layer of the immobilization medium 142 and thusreach the reagent medium 86.

Finally, the reaction used to detect glucose 194 in body fluid 190 isillustrated symbolically in FIG. 9 by a “reaction, arrow” 192. Theglucose 194 is oxidized via the enzyme GOD 186 to form gluconolacton,and oxygen is subsequently reduced to H₂O₂ by the enzyme GOD 186.Subsequently, the H₂O₂ is then catalytically oxidized by the brownstone184, and in the process the electrons are transferred onto the outgoinggold wire 180 via the carbon particles 182 that are in contact with thebrownstone 184. The potential of the gold wire 180 (or of the entireworking electrode 16), thus influenced, can be detected in the waydescribed above, for example by an amperometric measurement, and it ispossible from this to infer the concentration of the glucose in the bodyfluid 190.

The features disclosed in the above description, the claims and thedrawings may be important both individually and in any combination withone another for implementing the invention in its various embodiments.

It is noted that terms like “preferably”, “commonly”, and “typically”are not utilized herein to limit the scope of the claimed invention orto imply that certain features are critical, essential, or evenimportant to the structure or function of the claimed invention. Rather,these terms are merely intended to highlight alternative or additionalfeatures that may or may not be utilized in a particular embodiment ofthe present invention.

For the purposes of describing and defining the present invention it isnoted that the term “substantially” is utilized herein to represent theinherent degree of uncertainty that may be attributed to anyquantitative comparison, value, measurement, or other representation.The term “substantially” is also utilized herein to represent the degreeby which a quantitative representation may vary from a stated referencewithout resulting in a change in the basic function of the subjectmatter at issue.

Having described the present invention in detail and by reference tospecific embodiments thereof, it will be apparent that modification andvariations are possible without departing from the scope of the presentinvention defined in the appended claims. More specifically, althoughsome aspects of the present invention are identified herein as preferredor particularly advantageous, it is contemplated that the presentinvention is not necessarily limited to these preferred aspects of thepresent invention.

1-14. (canceled)
 15. A method of producing an electrochemical sensor fordetermining an analyte concentration in a body tissue or a body fluid,comprising the following steps: providing at least two electrodes andcoating at least one of the at least two electrodes with a reagentmedium for detecting the analyte; assembling a slab-shaped electrodepack by providing an isolation element having a profiled shape andhaving at least two holding compartments, and extending the at least twoelectrodes along the isolation element into respective ones of theholding compartments; subjecting either individual ones of the at leasttwo electrodes or the electrode pack to an immobilization medium coatingoperation; and feeding the electrode pack to a cut-to-length operationfor separation.
 16. The method as claimed in claim 15, furthercomprising the step of passing the at least one of the two electrodesthrough a drying station after the step of coating with the reagentmedium.
 17. The method as claimed in claim 15, wherein one or both ofthe step of coating with the reagent medium and the step of subjectingto the immobilization medium coating operation are carried out by use ofone of an annular nozzle coating method and an electroplating method.18. The method as claimed in claim 17, wherein the step of coating withthe reagent medium comprises use of a first annular nozzle forsubstantially wetting the surface of the at least one of the at leasttwo electrodes.
 19. The method as claimed in claim 17, wherein the stepof subjecting to the immobilization medium coating operation comprisesuse of a second annular nozzle for substantially coating the individualones of the at least two electrodes or the electrode pack with animmobilization medium.
 20. The method as claimed in claim 15, whereinthe cut-to-length operation comprises separating individual sections ofthe electrode pack into application-specific lengths.